Apotysis programmed cell death may increase as a result of the deranged metabolic staet such as elevation in glucose and free fatty acids.

Amyloid deposits provides another plausible mechanism to explain a portion of the reduced B-cell mass.

The exact mechanism for pathogenesis of impairments to B-cell function in type 2 diabetes is not known. A model for the interaction of dietary fat, glucose and islet amyloid is possible.

An individual who is genetically determined to be at risk of developing type 2 diabetes

A prolonged increase of dietary fat intake

Induces B-cell dysfunction

This reduction in function results in reduced insulin secretion that in turn results in hyperglycemia.

This also results in changes to how the B-cell handles IAPP and allows islet amyloidgenesis to occur.

As these deposits increase, they replace B-cell mass further aggravating the ability of the islet to produce and secrete insulin

Sustain hyperglycemia in the face of impaired B-cell function further aggravates B-cell function as a result of “glucose toxicity.”

These effects feed forward aggravating the clinical syndrome and in most individuals requiring increases in therapy aimed at reducing hyperglycemia.

The future for preventing the progressive B-cell failure of type 3 diabetes

A number of possible mechanism for B-cell dysfunction of type 2 diabetes.

Hyperglycemia and free fatty acids contributing would imply that aggressive control of both would result in improved insulin release and prevention of progression.

UKPDS showed a continuation of the decline of B-cell function even with excellent control of glucose and free fatty acids.

The effect of control of lipids is yet to be determined.

As the deposition of islet amyloid would be predicted to result in an ongoing loss of B-cell mass, it is possible that a small nidus of amyloid could be sufficient to explain the early progressive failure of B-cell function observed in type 2 diabetes.

Inhibition of the amyloidogenic process may well require the development of inhibitors that prevent the binding of secreted IPAA to formed fibils, well before large amounts of amyloid are visible by light microscopy.